Phosphorothioamides

ABSTRACT

Antibacterial phosphorothioamides are prepared by the reaction of phosphorothiocyanates with hydrazine or hydrazides.

The invention described herein was made in the course of work under agrant or award from the Department of Health, Education and Welfare.

This is a continuation of application Ser. No. 180,509, filed Sept. 14,1971, and now abandoned, which was a division of application Ser. No.852,945, filed Aug. 25, 1969, now U.S. Pat. No. 3,660,413.

This invention relates to novel phosphorothioamide compounds exhibitingantibacterial activity.

The phosphorothioamide compounds of the invention are of the generalformula

    (RO).sub.2 PONHCSY,

    ropo(nhcsy).sub.2

and

    PO(NHCSY).sub.3

wherein Y is H, N(CH₂)₂, NHNHC₆ H₅, NHNHCOOR or NHNHCOC₅ H₄ N and R islower alkyl. As used herein, the term "lower alkyl" embraces alkylradicals, branched or straight-chain, having 1-4 carbon atoms inclusive,e.g., methyl, ethyl, propyl, isopropyl and the butyls.

The phosphorothioamide compounds of the invention are generally preparedby the reaction, usually condensation, of a phosphorothiocyanate with ahydrazine or hydrazide. The reaction is usually effected in the presenceof an inert solvent, e.g., ether or carbon tetrachloride, in the cold byadding a solution of one of the reactants to the other dissolved in thesame solvent chilled to about 5°-10° C. The product generallyprecipitates from the reaction mixture but can also be recovered byevaporation of the product. The crude product is purified by solventrecrystallization, e.g., ether-alcohol.

Representative compounds of the invention were screened against threegram-positive and gram-negative microorganisms using the agardiffusion-filter paper disc method and found to exhibit significantantibacterial activity.

EXAMPLE 1. (C₂ H₅ O)₂ PONHCHS

To a chilled solution of diethyl phosphoroisothiocyantidate (C₂ H₅ O)₂PONCS, Can. J. Chem., 37, 525 (1959), dissolved in chilled ether wasgradually added an equimolar quantity of hydrazine dissolved in the samesolvent. After separation and recrystallization, the(C₂ H₅ O)₂ PONHCHSproduct melted 129° C with decomposition.

Reduction of the phosphoroisothiocyantidate reactant and the sameproduct was obtained when 4-methyl-3-thiosemicarbazide was substitutedfor hydrazine.

EXAMPLE 2. (C₂ H₅ O)₂ PONHCSNHNHC₆ H₅

Using the procedure of the previous example, phenylhydrazine wascondensed with diethyl phosphoroisothiocyantidate to give (C₂ H₅ O)₂PONHCSNHNHC₆ H₅ melting 125° C with decomposition.

Similar products are obtained when phenylhydrazine bearing substituentssuch as alkyl, halo, alkoxy and the like on the phenyl ring issubstitutedfor phenylhydrazine.

EXAMPLE 3. (C₂ H₅ O)₂ PONHCSNHNHCOOC₂ H₅

Using the procedure of the previous examples, ethyl carbazate H₂NNHCOOC₂ H₅ was condensed with diethyl phosphoroisothiocyantidate togive (C₂ H₅ O)₂ PONHCSNHNHCOOC₂ H₅ melting 147° C with decomposition.

EXAMPLE 4. (C₂ H₅ O)₂ PONHCSNHNH-4-COC₅ H₄ N

Using the procedure of the previous examples, but no solvent,pyridine-4-carboxylic acid hydrazide H₂ NNH-4-COC₅ H₄ N wascondensedwith diethyl phosphoroisothiocyantidate to give (C₂ H₅ O)₂PONHCSNHNH-4-COC₅ H₄ N melting 147° C with decomposition.

EXAMPLE 5. C₂ H₅ OPO(NHCSNHNHCOOC₂ H₅)₂

To a chilled solution of ethyl phosphorodiisothiocyantidate C₂H₅OPO(NCS)₂, Saunders et al., J. Chem. Soc., 699 (1948), dissolved inchilled ether was gradually added a solution containing twice theequimolar quantity of ethyl carbazate. Unlike the other examples, 1hour'sheating at 35° C was required to complete the reaction. Afterseparation and recrystallization, the C₂ H₅ OPO(NHCSNHNHCOOC₂ H₅)₂product decomposed about 80° C before melting.

EXAMPLE 6. C₂ H₅ OPO(NHCSNHNH-4-COC₅ H₄ N)₂

Using the procedure of the previous example, but acetonitrile as thesolvent, pyridine-4-carboxylic acid hydrazide was added to ethylphosphorodiisothiocyantidate to give C₂ H₅ OPOCNHCSNHNH-4-COC₅ H₄ Ndecomposing about 105° C before melting.

EXAMPLE 7. C₂ H₅ OPO(NHCSNHNHCOOC₂ H₅)(NHCSNHNHC₆ H₅)

Following the general procedure, equimolar quantities of phenylhydrazineand ethyl carbazate were sequentially added to a solution of ethylphosphorodiisothiocyantidate to give C₂ H₅ OPO(NHCSNHNHCOOC₂H₅)(NHCSNHNHC₆ H₅) which separated as a yellow oil before solidifying.The solid decomposed about 65° C before melting.

EXAMPLE 8. C₂ H₅ OPO(NHCHS)[NHCSN(CH₂)₂ ]

Essentially following the procedure of the previous example, ethanethioland then aziridine were added to ethyl phosphorodiisothiocyantidate inether. Reduction followed by condensation gave C₂ H₅OPO(NHCHS)[NHCSN(CH₂)₂ ] which decomposed about 147° C before melting.

EXAMPLE 9. PO(NHCSNHNHCOOC₂ H₅)₃

To a chilled solution of phosphinylidyne triisothiocyanate PO(NCS)₃,Saunders et al, J. Chem. Soc., 699 (1948) dissolved in chilled ether wasgradually added a solution containing triple the equimolar quantity ofethyl carbazate. After separation and recrystallization, thePO(NHCSNHNHCOOC₂ H₅)₃ product decomposed about 53° Cbefore melting.

In general, all of the products described were analyzed for and gavesatisfactory C, H and N analyses. Infrared spectra of the products on aBeckman spectrophotometer gave the expected absorptions. All productsdecomposed on melting or decomposed over a wide range before melting.

The antibacterial spectra were determined by saturating 12.7 mm filterpaper discs with 2 drops of an aqueous of alcoholic solution orsuspensionof the compound (20 mg/ml) and placing these on nutrient agarseeded with 48-hour nutrient culture broths of the test organisms (0.5ml). The zones of inhibition around the discs were measured after 4 daysof incubation at37° C. The first value given in the table below is thezone of complete inhibition; the value in parentheses which follows isthe zone ofcomplete and partial inhibition also in millimeters.

    __________________________________________________________________________    Compound                                                                           Solvent                                                                            M. smegmatis                                                                         S. aureus                                                                           γ-Strep.                                                                      E. coli                                                                            P. vulgaris                                                                          Ps. aeruginosa                       __________________________________________________________________________    1    EtOH 25 (35)                                                             1    H.sub.2 O                                                                          17 (25)                                                             2    EtOH 25 (33)                                                                              20    24                                                     4    EtOH 42 (54)                                                                              19    20    18 (22)                                                                            19     19                                   5    H.sub.2 O                                                                          15 (21)                                                                              20                                                           6    H.sub.2 O                                                                          36 (39)                                                             7    EtOH 18     17                      15                                   9    H.sub.2 O                                                                          19     18                      15                                   __________________________________________________________________________

I claim:
 1. C₂ H₅ OPO(NHCHS) [NHCSN(CH₂)₂ ].